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At least 109 records · Page 6Linked to original sources
PubMed1998

Identification and haplotype analysis of apolipoprotein B-100 Arg3500-->Trp mutation in hyperlipidemic Chinese.

DNA screening for apolipoprotein (apo) B-100 mutations was performed in hyperlipidemic Chinese. The apo B-100 gene segment surrounding previously identified familial defective apo B-100 (FDB) mutations was amplified by PCR and subjected to single-strand conformation polymorphism (SSCP) analysis. One subject's aberrant SSCP band was cloned and sequenced to study the molecular lesions. A recurrent ArgCGG-to-TrpTGG mutation (R3500W) in the codon 3500 of the apo B-100 gene was identified. The C-to-T transition creates a NlaIII site and permits rapid restriction analysis of the mutation. A total of 373 hyperlipidemic patients and 309 controls were screened for R3500W. Nine unrelated subjects were shown to be heterozygous for the mutation, and no R3500W carriers were found in the control group (P = 0.004). Six polymorphic markers, including five restriction fragment length polymorphisms and one hypervariable repeat region, were used for haplotype analysis on the mutant allele. In two families, the R3500W mutation could be unambiguously assigned to a unique haplotype XbaI-/MaeI+/MspI+/EcoRI+/ Eco57I+/34 3'HVR repeats; in the other seven unrelated heterozygotes, this finding was consistent when an unequivocal haplotype was deduced. The results suggest that all R3500W alleles are identical by descent in our population. The fact that the same mutant allele was identified in other Asians with FDB indicates a common Asian origin for the R3500W mutations.

Adult↗
PubMed1998

Familial mitochondrial DNA depletion in liver: haplotype analysis of candidate genes.

Two sons and one daughter of healthy consanguineous parents presented with fatal hepatic failure in association with severe depletion of mitochondrial (mt)DNA in liver; a third son is healthy. Other published cases of mtDNA depletion concern single members of a family, which excludes the use of haplotype analysis. In the family presented here, the inheritance of the genes for mitochondrial transcription factor A (mtTFA), nuclear respiratory factor 1 (NRF-1), mitochondrial single-stranded DNA-binding protein (mtSSBP), and endonuclease G (EndoG) was studied using microsatellite markers linked to these genes. The inheritance of the gene for mtDNA polymerase (pol gamma) was studied using a polymorphic CAG repeat present within the coding region of the gene. EndoG and mtSSBP were excluded, but mtTFA remains a candidate. Pol gamma or NRF-1 involvement would be compatible only with autosomal dominant inheritance. Coding sequence analysis of NRF-1 and mtTFA revealed no novel mutations in affected individuals.

Chromosomes, Human↗
PubMed2004

Transmission disequilibrium test and haplotype analysis of the NOTCH4 gene in Japanese patients with schizophrenia.

A recent study reported that the NOTCH4 gene was highly associated with schizophrenia in the British population. To confirm this association for another population, a case-control study was conducted and a transmission disequilibrium test (TDT) analysis was performed on a group of Japanese subjects (235 pairs of schizophrenia patients and controls, and 78 trios consisting of probands and their parents) using two single nucleotide polymorphisms and three microsatellite markers for the NOTCH4 gene. Haplotype analysis was also studied in case-control and family based data sets. In all markers except for (CTG)n (P = 0.012, before correction for multiple testing), no differences were found in the case-control study. The TDT analysis also revealed only a weak transmission disequilibrium in (TTAT)n (genotype-wise P = 0.012). The finding of the present study could not support the original findings that the NOTCH4 gene itself is associated with susceptibility to schizophrenia.

Adult↗
PubMed2002

Mutational and haplotype analysis of AGL in patients with glycogen storage disease type III.

Glycogen storage disease type III (GSD III) is a rare autosomal recessive inherited disorder caused by a deficiency of the glycogen-debranching enzyme (AGL). We investigated two GSD III patients and identified four different mutations. Nucleotide sequence analysis revealed patient 1 of Chinese descent to be a compound heterozygote for a novel nonsense mutation, R34X, and the splicing mutation (IVS32-12A > G) reported in a Japanese patient. Patient 2 of Japanese origin was found to be compound heterozygous for a novel nonsense mutation, Y1148X, and the splicing mutation (IVS14+1G > T) that we had described previously. To determine whether splicing mutations occurred independently, we performed intense AGL haplotype analysis using 21 intragenic polymorphic markers plus a novel polymorphism IVS32-97 A/G in the vicinity of the IVS32 splicing mutation. Patient 1 of Chinese origin and the Japanese patient homozygous for the IVS32-12A > G were found to have different haplotypes, indicating the IVS32-12A > G mutation to be a recurrent mutation. This is the first recurrent mutation established by intense haplotyping in the AGL gene.

Adult↗
PubMed1999

Detailed haplotype analysis in Ashkenazi Jewish and non-Jewish British dystonic patients carrying the GAG deletion in the DYT1 gene: evidence for a limited number of founder mutations.

The DYT1 gene on human chromosome 9q34 appears to be responsible for most cases of early onset primary torsion dystonia (PTD) both in Ashkenazi Jewish (AJ) and in non-Jewish patients. Previous haplotype analysis in a 2 cM region surrounding the DYT1 gene showed that a single founder mutation (DYT1AJ) was responsible for most cases of early onset PTD in the North American AJ population and refined the most likely location of the gene to a 150 kb interval between the marker loci D9S2161 and D9S63. Recently, the majority of cases of early onset PTD in both AJ and non-Jewish patients were found to carry a unique 3-bp (GAG) deletion in the coding region of the DYT1 gene. This deletion appears to have arisen more than once, suggesting independent mutational events. In this study, we analysed the haplotypes surrounding DYT1 in 9 AJ and 15 non-Jewish British patients carrying the GAG deletion in the DYT1 gene. We found that all AJ British patients carried the same haplotype as the North American Jews, sustaining the theory that the current British AJ community descends from the same small group of individuals as the North American Jewry. Furthermore, in the non-Jewish British patients, only a limited number of distinct founder mutations was observed. This supports the hypothesis that the GAG deletion in the DYT1 gene is not a very frequent mutation, and that it has arisen only a limited number of times throughout the centuries.

Alleles↗
PubMed2006

Haplotype analysis of common vitamin D receptor variants and colon and rectal cancers.

Inherited variants of the vitamin D receptor (VDR) gene may influence cancer risk by altering the effect of vitamin D on cell growth and homeostasis. Studies have examined genotypes for common VDR polymorphisms, including a single nucleotide polymorphism (SNP) detected by Bsm1, a polyadenosine [poly(A)] repeat polymorphism, and a SNP detected by Fok1, as candidates for susceptibility to cancer, but most have not evaluated haplotypes for these markers. We investigated haplotypes for these polymorphisms in case-control studies of colon cancer (1,811 cases and 1,451 controls) and rectal cancer (905 cases and 679 controls). We used the expectation-maximization algorithm to estimate haplotypes for White, Hispanic, African-American, and Asian subjects, tested for differences in VDR haplotype distribution, and calculated odds ratios (OR) for association between haplotype and cancer. The distribution of haplotypes differed by race or ethnic group, but four common haplotypes accounted for the majority of alleles in all groups. VDR haplotype distributions differed between colon cancer cases and controls (P = 0.0004). The common haplotype bLF, containing Bsm1 b (Bsm1 restriction site present), poly(A) long (18-22 repeats), and Fok1 F (restriction site absent) was associated with increased risk of colon cancer, OR 1.15 (95% confidence interval, 1.03-1.28), as was the rare haplotype BLF, containing Bsm1 B (restriction site absent), poly(A) long, and Fok1 F (OR, 2.40; 95% confidence interval, 1.43-4.02). No case-control differences were detected for rectal cancer. In this analysis, haplotypes of the VDR influenced risk of colon cancer, but haplotype variables had only slightly better ability to explain case-control differences than genotype variables.

Adult↗
PubMed1988

The human tyrosine aminotransferase gene: characterization of restriction fragment length polymorphisms and haplotype analysis in a family with tyrosinemia type II.

Deficiency in hepatic tyrosine aminotransferase (TAT) causes tyrosinemia type II, an autosomal recessively inherited disorder. Using a TAT cosmid clone, we have identified an MspI restriction fragment length polymorphism (RFLP) 5' to the TAT gene, with allele frequencies of 0.63 and 0.37. Analysis of the cloned maternal and paternal TAT alleles from a patient with tyrosinemia type II led to the identification of a HaeIII RFLP at the 3' end of the TAT gene, with allele frequencies of 0.94 and 0.06. The two RFLPs are 27 kb apart and in no allelic association. From haplotype frequencies, a polymorphism information content (PIC) value of 0.44 was obtained. The two RFLPs have allowed the unambiguous identification of the mutant TAT alleles in the patient's pedigree by haplotype analysis.

Amino Acid Metabolism, Inborn Errors↗
PubMed2002

Haplotype analysis excludes the functional protoporphyrinogen oxidase promoter polymorphism -1081G>A as a modifying factor in the clinical expression of variegate porphyria.

Variegate porphyria (VP) is caused by the founder-type protoporphyrinogen oxidase (PPOX) gene mutation R59W in the majority of South African patients. VP is inherited as an autosomal dominant disease with incomplete penetrance and no genotype-phenotype association has been established to date. In an attempt to determine whether a relatively common mutation in the promoter region of the gene (-1081G>A) represents a low-expression allele that may influence clinical manifestation of the disease when inherited from the non-carrier (R59W-negative) parent, we have studied the effect of the mutated allele using an in vitro luciferase assay. Haplotype analysis was furthermore used to evaluate the added information obtained by considering the possible influence of this mutation in combination with a polymorphism in intron 2 (206G>C) of the gene in a genotype-phenotype correlation study. Although the mutation at nucleotide -1081 resulted in a significant reduction in transcriptional activity relative to the reference wild type, no evidence could be obtained that a specific haplotype inherited from the normal parent affects clinical expression of the disease. We thus conclude that other factors such as modifier loci unrelated to the PPOX gene may determine clinical manifestation of VP.

Adult↗
PubMed1995

CFTR haplotype analysis reveals genetic heterogeneity in the etiology of congenital bilateral aplasia of the vas deferens.

Congenital bilateral aplasia of the vas deferens (CBAVD) was suggested to be a mild form of cystic fibrosis (CF). Mutation analysis of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in males with CBAVD revealed that in some males CBAVD is caused by two defective CFTR alleles. The genetic basis of CBAVD in the other males and its association with CF remained unclear. We undertook this study to test the hypothesis of commonality of CBAVD and CF by haplotype analysis, in the CFTR locus, of males suffering from CBAVD and of their families. According to the hypothesis of commonality of CBAVD and CF, two brothers with CBAVD are expected to carry the same two CFTR alleles, while their fertile brothers are expected to carry at least one different allele. Eleven families were studied, of which two families, with unidentified CFTR mutations, did not support this hypothesis. In these families two brothers with CBAVD inherited different CFTR alleles. Their fertile brothers inherited the same CFTR alleles as their brothers with CBAVD. These results provide evidence for genetic heterogeneity in CBAVD. Though in some families CBAVD is associated with two CFTR mutations, we suggest that in others it is caused by other mechanisms, such as mutations at other loci or homozygosity or heterozygosity for partially penetrant CFTR mutations.

Congenital Abnormalities↗
PubMed2004

Molecular basis of ESD*5 and ESD*7 and haplotype analysis with new polymorphisms in introns.

The two polymorphic alleles of esterase D (ESD), ESD*5 and ESD*7, are specific to Europeans and Asians, respectively. In this study the molecular basis was characterized: ESD*5, arising from ESD*1, has a G to A transition, resulting in Gly257(GGT) --> Asp(GAT); and ESD*7, originating from ESD*2, has an A to G transition, resulting in Asp231(GAT) --> Gly(GGT). Glycine is also involved in the common ESD*1/ESD*2 polymorphism [Gly190(GGA) --> Glu(GAA)]. Haplotype analysis using a few novel intragenic polymorphisms showed strong associations among polymorphic sites, suggesting that recombination has been less frequent in the human ESD gene, although it spans about 25 kb from exon 1 to exon 10. A marked difference was observed in the distribution of haplotype frequencies between Germans and Japanese.

Animals↗
PubMed2003

Haplotype analysis with 14 Y-STR loci using 2 multiplex amplification and typing systems in 2 regional populations in Japan.

In this study 14 Y-STR loci (DYS393, DYS19, DYS391, DYS437, DYS435, DYS439, DYS389II, DYS438, DYS436, DYS390, Y-GATA-H4, DYS385, Y-GATA-A7.1 and DYS392) were analysed in 207 Japanese males from Honshu (main island of Japan, Nagoya City) and 87 Japanese males from Okinawa (southernmost islands of Japan) using two multiplex PCR typing systems, a novel 10-plex amplification system and a new commercially available 6-plex typing kit which had two loci in common. The allele frequency distributions were similar at almost all of the 14 loci. Of the haplotypes observed, 244 were unique in both Japanese populations and 17 haplotypes were observed more than once but the 2 populations shared only 7 haplotypes. The haplotype diversities for the 14 loci were 0.9987 and 0.9976 in Honshu and Okinawa Japanese, respectively. The haplotype analysis at 14 Y-STR loci would be useful for personal identification in forensic fields and for population genetics because of the high divergence of these haplotypes.

Chromosomes, Human, Y↗
PubMed1998

Antithrombin cambridge II (Ala384Ser): clinical, functional and haplotype analysis of 18 families.

Thirty-one individuals from 18 unrelated families with antithrombin deficiency have been identified as having a single point mutation within codon 384 (13268 GCA-->TCA) resulting in an alanine to serine substitution. Six families (11 individuals) were identified by the screening of individuals with thromboembolic disease or with a family history of thromboembolic disease, whilst the remaining 12 families (20 individuals) were identified by screening of asymptomatic blood donors. Four individuals had a history of venous thrombotic disease, a further 2 gave a history of superficial thrombophlebitis but the remaining 25 individuals were asymptomatic. Affected individuals demonstrated normal immunological levels of antithrombin but a decrease in anti-IIa activity in the presence of heparin. Haplotype analysis was used to examine the possibility of a founder effect to explain the high frequency of this non-CpG mutation. 29/31 individuals showed a single common "core" haplotype, the only variation existing in the number of copies of an (ATT)n repeat polymorphism--13, 14, 15 or 17. The results suggest that at most there are four independent origins for this mutation.

Alanine↗
PubMed1999

Intragenic single nucleotide polymorphism haplotype analysis of SUR1 mutations in familial hyperinsulinism.

Familial hyperinsulinism (HI; MIM# 256450) is an autosomal recessive disorder of pancreatic beta-cell function, characterized by inadequate suppression of insulin secretion despite severe recurrent fasting hypoglycemia. Subtotal pancreatectomy is frequently required to prevent permanent neurologic sequelae. The incidence of HI in the Caucasian population is estimated at 1:50,000, however an apparent increased incidence among Ashkenazi Jews and Saudi Arabian Arabs has been reported. A locus for HI was assigned by linkage analyses to human chromosome 11p15.1. The sulfonylurea receptor (MIM# 600509, SUR1) and the potassium channel, inwardly rectifying, subfamily J member 11 (MIM# 600937, KIR6.2) genes, 2 components of the beta-cell K(ATP) channel, are clustered in this chromosomal region, and mutations in these genes have been implicated in HI. We previously demonstrated that two mutations in the SUR1 gene are present on approximately 88% of HI-associated chromosomes in Ashkenazi Jewish patients. Haplotype analysis with microsatellite markers flanking the gene revealed that one mutation (delF1388), reported only in Ashkenazi probands, occurred on two related extended haplotypes. By contrast, the second, more common mutation (3992-9g-->a) was associated with nine different intergenic haplotypes and has been reported in non-Jewish HI patients as well. In this study, we evaluated disease-associated chromosomes from 41 Ashkenazi Jewish and 2 non-Jewish HI patients carrying the 3992-9g-->a mutation by assessing haplotypes defined by nine common single nucleotide polymorphisms (SNPs), six in the SUR1 gene, and three in the KIR6.2 gene. Our results indicate that all 54 chromosomes carrying the 3992-9g-->a mutation in the Jewish patients appear to have originated from one founder mutation, whereas the same mutation on chromosomes from non-Jewish patients originated independently. Furthermore, our findings have implications concerning the HI-associated chromosomes on which no mutation has been identified.

ATP-Binding Cassette Transporters↗
PubMed1994

Haplotype analysis of MEN 2 mutations.

Multiple endocrine neoplasia type 2 (MEN 2) is a dominantly inherited cancer syndrome which affects thyroid C cells, and with variable frequency, the adrenal medulla, parathyroid and enteric autonomic ganglia. The syndrome is due to germline mutation in the receptor tyrosine kinase gene, RET. We have recently shown an unexpected correlation between one particular RET mutation, cys634-->arg, and the probability of parathyroid involvement in families with MEN 2A. Here we use haplotype analysis in the families to show that this correlation is not explained by a single founder chromosome which carries both the cys634-->arg mutation and a separate allele conferring susceptibility to parathyroid abnormality, but is probably due to the cys634-->arg mutation itself. The results also indicate that new mutations to MEN 2 are not infrequent.

Amino Acid Sequence↗
PubMed2003

Haplotype analysis of the growth hormone releasing hormone receptor locus in three apparently unrelated kindreds from the indian subcontinent with the identical mutation in the GHRH receptor.

The growth hormone releasing hormone receptor (GHRHR) plays a critical role in growth. We identified three nominally unrelated kindreds harboring the identical mutation (E72X) in GHRHR, the gene that encodes GHRHR; all three families originated in the Indian subcontinent. Because of the relative geographic proximity of these populations, we employed haplotype analysis in the region of GHRHR to determine the likelihood that this mutation occurred in a common ancestor rather than having occurred on separate occasions in different individuals. Members of all three kindreds segregating the E72X mutation were genotyped for highly polymorphic dinucleotide repeat microsatellites in a 15.5 centimorgan (cM) region around GHRHR on chromosome 7p15. We conclude that the affected individuals share a common ancestor, and we use the association with linked markers to estimate the age of this unique mutation.

Chromosomes, Human, Pair 7↗
PubMed2004

Single nucleotide polymorphism and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene in suicide victims.

BACKGROUND: Tryptophan hydroxylase, the rate-limiting enzyme in the biosynthesis of serotonin, represents a major candidate in numerous genetic association analyses of suicidal behavior; however, the results are so far inconclusive. Recently, a second tryptophan hydroxylase isoform (TPH2) was identified in mice, which was exclusively present in the brain. In a previous postmortem study of our own group, we could demonstrate that TPH2 is also expressed in the human brain but not in peripheral tissues. METHODS: We performed single nucleotide polymorphisms, haplotypes, and linkage disequilibrium studies on 263 suicide victims and 266 healthy control subjects with 10 single nucleotide polymorphisms in the TPH2 gene. RESULTS: Significant association was detected between one single nucleotide polymorphism (p = .004, global p = .01) and suicide. Additionally, haplotype analysis also produced support for association (p < .0001, global p = .0001). CONCLUSIONS: This is the first report about an association between TPH2 gene polymorphisms and completed suicide. Our findings provide evidence for an involvement of genetic variants in the TPH2 gene in suicidal behavior. These results might open up new research strategies for the analysis of the observed disturbances in the serotonergic system in several other psychiatric disorders.

Adolescent↗
PubMed1998

Recurrence of the D409H mutation in Spanish Gaucher disease patients: description of a new homozygous patient and haplotype analysis.

Gaucher disease results, in most patients, from mutations in the gene encoding glucocerebrosidase. Mutation D409H is the third most frequent in Spanish patients, accounting for 5.7% of all mutated alleles. This allele is associated mainly with the neurological forms of the disease. Recently, homozygosity for the D409H mutation has been associated with a particular phenotype, including specific cardiovascular symptoms. Here we report a second Spanish patient bearing the D409H/D409H genotype with a very early manifestation of the disease. The patient started enzyme replacement therapy at 3 months of age. A common origin for the Spanish D409H alleles was ruled out by haplotype analysis using an internal polymorphism of the glucocerebrosidase gene and two external microsatellite markers.

Gaucher Disease↗
PubMed2006

Breakpoint cloning and haplotype analysis indicate a single origin of the common Inv(10)(p11.2q21.2) mutation among northern Europeans.

The pericentric inv(10)(p11.2q21.2) mutation has been frequently identified in cytogenetic laboratories, is phenotypically silent, and is considered to be a polymorphic variant. Cloning and sequencing of the junction fragments on 10p11 and 10q21 revealed that neither inversion breakpoint directly involved any genes or repetitive sequences, although both breakpoint regions contain a number of repeats. All 20 apparently unrelated inv(10) families in our study had identical breakpoints, and detailed haplotype analysis showed that the inversions were identical by descent. Thus, although considered a common variant, inv(10)(p11.2q21.2) has a single ancestral founder among northern Europeans.

Base Sequence↗